Exam 1 Flashcards
What is drug distribution?
The post absorptive transfer of drug from one location in the body to another
Why is one compartment model not adequate to describe drug distribution?
Because drug distribution would be assumed to occur instantaneously at time = 0
Therefore multi compartmental models are required to describe drug distribution
What are the two components of drug distribution?
Rate and extent of distribution
What can estimate the rate of drug transfer between compartments?
Distribution clearance (CLd)
Also known as inter compartmental clearance or rate of perfusion (Q)
What does volume of distribution assess?
The extent of drug distribution
What are the two steps of distribution?
Presentation of the drug to the tissue by the blood
Diffusion or uptake of drug from the blood to the tissue
The rate of distribution is limited by the slower of these steps
What does hydrostatic pressure do for movement of the drug?
Creates the pressure gradient between the arterial end entering the tissue and the venous capillaries leaving the tissue
What is hydrostatic pressure responsible for?
Penetration of water soluble drugs into spaces between endothelial cells and maybe into the lymph
What is the rate of tissue perfusion?
Q
The rate of drug presentation to the tissues
What is the unit of tissue perfusion?
Described by the volume of blood delivered to the tissue per unit time
mL/min
TF: The rate of drug presentation to different tissues will vary from one to another based on the rate of tissue perfusion.
True
What happens to drug distribution to patients with congestive heart failure?
In perfusion controlled drugs, there will be an accumulation of drug in the body and an increase in toxicity, so the dose would need to be lowered
There would be a decrease in perfusion rate
What happens once the drug molecule arrives close to tissue site?
They rapidly diffuse into interstitial fluid of capillaries and further diffuse from the IF across the tissue membrane to be in the tissue, driven by the passive diffusion across the epithelial membrane
What kind of drugs are diffusion controlled?
Polar molecules (cannot pass through membrane readily)
What kind of drugs are perfusion controlled?
Non polar molecules
What happens to permeability of capillaries and cells when inflammation occurs?
It increases which allows polar molecules to pass through the membrane
Diffusion controlled
Permeability controlled
What does distribution half life represent?
Represents the time required for the plasma concentration to decline by 50% during the distribution phase
What is distribution half life used to determine?
How long a drug takes to distribute from central to peripheral compartment
In Cp=Ae-at+Be-Bt what does a represent?
The distribution of rate constant
How do you find t1/2 in two compartment model?
t1/2, alpha= 0.693/alpha
How do you find time to reach steady state in distribution?
tss=(t1/2,alpha)*5
When rate in = rate out
What is the extent of drug distribution?
The relative distribution of drug molecules between blasma and the rest of the body
What is the rate of distribution?
How fast the drug distribution takes place
What is the normal volume of plasma for an average healthy adult?
3L
What volume is in an average healthy adult of blood?
5L
What are the three physiological fluid volumes in which drugs distribute?
Plasma (3L)
Extracellular fluid (15L)
Total body fluid (42L)
How much interstitial water is in an average healthy adult?
12L
How much intracellular water is found in an average healthy adult?
27L
Where do the drug molecules distribute throughout after absorption, once the drug molecules are in systemic circulation?
Throughout the volume of plasma water
What happens to movement of drug when lipid solubility is increased?
Favoring drug movement OUTSIDE plasma
What happens to drug movement amount when molecular size is decreased?
Favoring movement of drug outside the plasma
What happens to drug movement when plasma protein binding is increased?
Restricts movement of drug outside plasma
What are the factors that determine the extent of drug distribution beyond plasma water?
Physiochemical properties of the drug
Permeability characteristics of the membrane
IF the drug is distributed only in the plasma what is the approximate Vd in an average person?
0.04 L/Kg
What kind of drugs would you want a drug limited to plasma distribution?
Anticoagulant, anemia
What are most drugs distributed throughout?
the volume of extracellular fluid (15L)
Why are most drugs distributed through the volume of extracellular fluid?
Because epithelial membrane of the capillary cells is very loose and permits passage of even polar and protein molecules
What is included in extracellular fluid?
Plasma and interstial water
What is the Vd in an average person for drugs that distribute in the extracellular fluid?
0.2L/Kg
What does a drugs’ ability to penetrate individual cell membrane depend on?
Physicochemical properties
Small lipophilic drugs penetrate biological membranes easily and distribute throughoutt the total body water (unless specialized uptake transporters then polar molecules and larger molecules can pass)
What does a drugs’ ability to penetrate individual cell membrane depend on?
Physicochemical properties
Small lipophilic drugs penetrate biological membranes easily and distribute throughoutt the total body water (unless specialized uptake transporters then polar molecules and larger molecules can pass)
What is the approximate Vd ina an average person for a drug that distribures in total body water?
0.6 L/Kg
What kind of drugs would go beyond total body fluid?
Highly lipophilic and with high tissue structure binding affinities
Very small molecular weight
TF: In reality the extent of volume distribution of many drugs is equal to the total body fluid?
False most are greater than the total body fluid
In addition to the available physiological volumes, drugs’ properties drive the extent of the drugs distribution
What kind of drugs are antibiotics for IV?
Aminoglycosides
Highly polar drugs
What is apparent volume of distribution?
The extent of drug distribution
What is Vd?
Hypothetical volume of fluid required to contain the total dose of a drug in the body at the same concentration as that present or measured in the plasma
How do you find Vd?
Vd= Amount of drug in the body/ Concentration in plasma
What is Vd affected by?
pathological conditions that disturb either body volumes (dehydration), plasma protein concentrations and binding, or tissue binding
What is Vd affected by?
pathological conditions that disturb either body volumes (dehydration), plasma protein concentrations and binding, or tissue binding
True false
Vd varies with body weight
True
What do we use to estimate the apparent Vd
Compartmental PK models are utilized best
True False: Vd is not constant for a drug
False
Vd is constant for a drug
Assuming normal physiologic and health conditions
True False: Vd is not constant for a drug
False
Vd is constant for a drug
Assuming normal physiologic and health conditions
How many different volumes of distribution are shown in plasma concentration time curve of drugs that display two or multi-compartment distribution models?
three
Characterized based on the time they occur after the dose
Why is Vss clinically important?
Because of physiological relevance reflecting the extent of drug distribution from the plasma pool into tissues
What are the two approaches for estimating Vss?
Based on 2 compartment system (Vc+VB)
Based on the extent of drug binding to plasma proteins with the actual plasma volume and the extent of drug binding to tissue proteins with the actual tissue volumes
At equilibrium between the plasma and tissues the extent of drug distribution depends on….?
It binding to plasma proteins
Blood cells
tissue structures
Actual total volumes of plasma and tissues
True False
Drug binding to plasma proteins and tissue structures have very important influence of drug distribution
True
How could Vd exceed physiological total body volume?
Because drug binding to peripheral tissue structures
What are the plasma proteins that could bind to drug molecules?
Albumin
Globulins
Alpha 1 acid glycoproteins
lipoproteins
What are the tissue structures that could bind to drug molecules?
Nucleic acids
Ligands
Calcified tissues
Adenosine triphosphate
What kind of drug can diffuse outside the plasma and participate in the concentration gradient that drives the distribution process?
Unbound or free portion of drug
Bound drugs cannot participate
Where is albumin synthesized?
In the liver
55% plasma proteins
A drug with 90% plasma protein binding but does not bind to tissue structures is how much unbound?
10%
What is the relationship between free concentrations of drug in the plasma and bound concentrations of drug in the tissues at steady state?
They are equal
At steady state what is the relationship between total concentration of drug in plasma compared to tissue in drugs that have high plasma protein binding?
Total concentration of drug (bound and unbound) i the plasma»_space;»» Total concentration of drug (bound and unbound) in the tissue
What restricts the distribution of drug outside of plasma while concentrating it in the plasma?
The strength of plasma protein binding
Causes Vd to be smaller values
What is the relationship between volume of distribution and half life?
The greater the volume of distribution the greater the half life
How do you find amount in the body?
A=Vd*Cplasma
Bd,ss=Vplasma+Vtissue*((fu,plasma/fu,tissue))
KNOW THIS
How do you find unbound plasma concentration?
=Cplasma*fu,plasma
How do you find unbound tissue concentration?
Ctissue*fu,tissue
In the plasma, drug exists in what 2 forms?
Unbound and bound forms
How does binding occur?
Very rapidly and completley reversible
How does equilibrium between the unbound and bound forms establish?
Quickly
If the unbound drug concentration decreases, bound drug dissociates rapidly to restore equilibrium
What is the clinically measured concentration?
Unbound and bound concentration
What is the equilibrium of unbound and bound drug?
Drug unbound + plasma protein total = Drug plasma protein complex bound
What does the unbound free drug concentration do?
Diffuses across membranes to the drug’s site of action
Interacts with the receptors to cause pharmacological and toxicological activities
Available for distribution and elimination
How can the unbound plasma drug concentrations be calculated?
Cp,u=Cp*fu,p
What is affinity?
The magnitude of the association constant
k1/k2
When does affinity increase?
K1»»»k2,
the ratio increases and drug binding to plasma protein is favored , the drug binds to plasma proteins extensively
k1/k2
When plasma protein binding increases in proportion to increase in drug concentrations, what happens to fu?
Remains constant over therapeutic plasma concentrations with a few exception drugs
When would albumin decrease in concentration?
Liver disease, age, pregnancy, burns, other trauma
Lower plasma proteins and more free drug
When would albumin synthesis increase?
Thyroid hormone
Corticosteroids
Growth hormone
Insulin
Increase in plasma proteins and binding
What kind of drugs bind to albumin?
Acidic
Glycoproteins are basic
When would AAG concentrations increase?
Physiological stress
(MI)
Cancer
Surgery
Increase binding
When would lipoproteins decrease in concentration?
Dieting and therapy with statins
When would lipoproteins increase in concentrations?
Alcoholism
Diabetes mellitus
Increase in binding
What would happen if you gave warfarin and asprin?
Asprin would replace warfarin in binding and would increase free warfarin which would increase toxicity
Binding of one drug may displace a second drug from its binding site(concentration dependent displacement)
What two factors cause a minimization clinical consequences of changes in plasma protein binding?
Increased elimination
Little change in drug concentrations outside the plasma
How does increase elimination decrease clinical consequences of changes in plasma protein binding?
Unbound drug is accessible to the elimination organs
WHen protein binding decreases, unbound drug concentration increases, proportional increase in elimination, eventually the unbound drug concentration in the plasma decreases to same value as that before the change in binding
Increase in unbound concentration is canceled out by increased elimination
How do you find loading dose?
LD=Vs*TargetCp
